Inadequate distribution of low-dose potent drugs is a constant threat to the uniform potency of tablets and capsules containing such drugs.
The greatest potential for drug-diluent segregation in a tablet system occurs with powder or particulate mixtures intended for direct compression or wet granulation in which the drug migration occurs (Dale E. Fonner et. al., Pharmaceutical Dosage Forms: Tablets, Volume 2, pp. 253.). European Patent Application 92103963.2, AKZO N. V. p. 6 describes the inadequate homogeneity encountered with compositions containing hydrous lactose DT (U.S. Pat. No. 4,544,554 etc. issued to Samuel A. Pasquale). The migration of a low-dose potent drug disrupts the distribution throughout the mix, giving rise to inconsistency in the content uniformity of the dosage form.
U.S. Pat. No. 3,568,828 issued to Leonard Joseph Lerner describes wet processes using potent drug substances such as estrogens with organic solvents such as chloroform. Such processes are now regarded as environmentally unsafe and can incur considerable manufacturing expenses, in that appropriate solvent scrubbing and/or explosion proof equipment must be acquired at substantial capital expenditure.
Estradiol and a number of other low-dose potent drugs precipitate in a variety of polymorphs and/or crystal habits. The changes in the crystal structure on drying can affect the bioavailability of the drug. It is well known in the literature that the micronized form is more bioavailable than larger drug particle size. This invention offers an important alternative to wet granulation, thus eliminating recrystallization and the issue of polymorphism and bioavailability. It also offers the choice of dry mixing or direct compression with materials other than the conventional spray dried polyalcohols or lactoses.